The extracellular domain of tumour necrosis factor-alpha (TNF-alpha) receptors have inhibitory properties against TNF-alpha. The relative ratio between ligand and ligand inhibitors may influence the outcome of meningococcaemia. To test this hypothesis, levels of TNF-alpha and of each of the soluble inhibitory fragments originating from two distinct TNF-alpha receptors (sTNF-RI and sTNF-RII) were measured in sera of children with severe meningococcaemia. On admission to the hospital the levels of sTNF-RI, -RII and TNF-alpha were markedly increased and all three correlated with the outcome of the disease. A correlation was found between TNF-alpha and sTNF-RI (P less than 0.001 by Pearson rank correlation coefficient) or sTNF-RII (P = 0.012). For TNF-alpha concentrations below 500 pg/ml, the increase of TNF-alpha was proportional to that of sTNF-RI and RII; however, when TNF-alpha levels exceeded 500 pg/ml, sTNF-RI and RII concentrations did not increase proportionally. At admission, in patients with fatal outcome, the ratios TNF-alpha/sTNF-RI and -RII were higher than in survivors. During the first 6 hr, the kinetics of TNF-alpha, sTNF-RI and -RII were different. Naturally occurring TNF-alpha inhibitors may play an important role in modulating the biological activity of TNF-alpha in severe meningococcaemia.